Cyclooxygenase (COX) inhibitors have an established place in the treatment of thrombotic and inflammatory diseases. Although randomized clinical trials have established that low dose aspirin is efficacious in the secondary prevention of stroke and myocardial infarction, it has been suggested that a syndrome of "aspirin resistance" constrains its efficacy in up to a third of aspirin users. We propose to determine the stability, specificity and consequent incidence of the "aspirin resistant" phenotype, to compare the ability of aspirin to prevent transient haemostatic activation by bacterial lipopolysaccharide (IPS) in "resistant" and "responsive" individuals, to define novel lipidomic and proteomic signatures of aspirin resistance and to relate conventional and novel biomarkers of this phenotype to a surrogate of clinical outcome- progression of atherosclerotic plaque burden. Specific Aim 1 addresses the incidence of a stable and specific phenotype of "aspirin resistance" in healthy volunteers given aspirin by measuring platelet aggregation and both ex vivo and in vivo indices of platelet prostaglandin production. Specific Aim 2 will determine the impact of a resistant phenotype on inhibition of evoked haemostatic activation by aspirin. The impact of low dose aspirin on the prevention of hemostatic activation by lipopolysaccharide in "resistant" and "responsive" volunteers will be studied to determine the impact of combined inhibition of COX-1 and COX-2 on haemostatic activation by IPS in these subsets, to identify novel proteomic and lipidomic signatures which identify individuals as "aspirin resistant", and to identify genetic variants of COX-1 which correspond to the resistant phenotype. Specific Aim 3 will relate prospectively individual biomarkers of the stable aspirin-resistant phenotype to carotid and coronary artery plaque progression, relate novel proteomic and lipidomic biomarkers of resistance to this clinical surrogate of cardiovascular disease in patients treated with aspirin, and initiate assessment of the correlation of genetic covariants of resistance with cardiovascular events in patients treated with aspirin.